Chromenylmethyl pyrimidinediamines as antibacterial agents

ABSTRACT

This invention is concerned with substituted chromene derivatives of the general formula (I)                    
     in which R 1 -R 4  are as defined in the specification and claims. The invention further relates to the pharmaceutically acceptable acid addition salts of these compounds, their use as therapeutically active substances; medicaments based on these substances, optionally in combination with sulphonamides, and their production; the use of these substances as medicaments and for the production of antibacterially-active medicaments; as well as the manufacture of the compounds of formula (I) and their pharmaceutically acceptable acid addition salts and intermediates for their manufacture.

This invention is concerned with substituted chromene derivatives of thegeneral formula

in which

R¹ represents alkyl or cycloalkylalkyl,

R² and R³ each independently represent alkyl or cycloalkyl or takentogether with the adjacent carbon atom represent a saturated 3- to6-membered carbocyclic or heterocyclic ring, the alkyl, cycloalkyl,carbocyclic or heterocyclic ring being unsubstituted or substituted, and

R⁴ represents hydrogen, halogen, cyano, alkyl, alkylthio, alkenyl,alkynyl, hydroxyalkyl, hydroxyalkynyl, alkoxyalkyl, alkoxyalkynyl,trialkylsilyl, aryl or heteroaryl,

and pharmaceutically acceptable acid addition salts of these compounds.

The above compounds are novel and possess valuable antibioticproperties. They can be used in the control and prevention of infectiousdiseases. In particular, they exhibit a pronounced antibacterialactivity, including against multi-resistant gram-positive strains, suchas Streptococcus pneumoniae and Staphylococcus aureus. These compoundscan also be administered in combination with known antibacteriallyactive substances and then exhibit a synergistic effect. Typicalcombination partners are e.g. sulphonamides, which can be admixed withthe compounds of formula I or their salts in various ratios.

Objects of the present invention are compounds of formula I and theirpharmaceutically acceptable acid addition salts per se and their use astherapeutically active substances; medicaments based on thesesubstances, optionally in combination with sulphonamides, and theirproduction; the use of these substances as medicaments and for theproduction of antibacterially-active medicaments; as well as themanufacture of the compounds of formula I and their pharmaceuticallyacceptable acid addition salts and intermediates for their manufacture.

The groups named above are defined below. In combined residues such ashydroxyalkyl, cycloalkylalkyl etc. the exemplification is to beunderstood accordingly.

The term “halogen” means fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine.

The term “alkyl” denotes a straight or branched chain hydrocarbon groupwhich carries up to and including 6, preferably 4 carbon atoms, if nototherwise specified. Examples are, e.g., methyl, ethyl, n-propyl,isopropyl, isobutyl, sec-butyl, t-butyl. The alkyl group beingoptionally substituted, e.g., by halogen (e.g. chlorine, bromine,fluorine); cyano; lower alkoxy (e.g. methoxy, n-butoxy); nitro; amino;lower alkoxycarbonylamino (e.g. t-butoxycarbonylamino); loweralkanoylamino (e.g. acetylamino).

The term “alkoxy” and “alkylthio” denote groups wherein the alkyl partis as defined above and which are attached via an oxygen or sulfur atom,respectively, examples of such groups are methoxy, ethoxy, n-propoxy,isopropoxy, isobutoxy, sec-butoxy, t-butoxy; and methylthio, ethylthio,n-propylthio, isopropylthio, isobutylthio, sec-butylthio, t-butylthio.

“Alkenyl” and “alkynyl” are unsaturated straight or branched chainhydrocarbon groups which carry up to and including 6, preferably 4carbon atoms having at least one double or triple bond, respectively,e.g. vinyl, 2-propenyl, 2,4-butadienyl, isopropenyl; 1-propynyl,2-propynyl, 1-butynyl, 3-butynyl. These groups may be unsubstituted orsubstituted. Examples of substituted alkynyl groups are, e.g.,3-hydroxy-1-propynyl, 3-hydroxy-1-butynyl, 3-methoxy-1-propynyl.

“Cycloalkyl” denotes a saturated carbocyclic group which carries 3 to 6carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.The cycloalkyl group being optionally substituted, e.g., by halogen(e.g. chlorine, bromine, fluorine); cyano; lower alkoxy (e.g. methoxy,n-butoxy); nitro; amino; lower alkoxycarbonylamino (e.g.t-butoxycarbonylamino); lower alkanoylamino (e.g. acetylamino).

“Cycloalkylalkyl” denotes the combination of cycloalkyl and alkyl asdefined above, e.g., cyclopropylmethyl, 2-cyclopropylethyl,cyclopentylmethyl.

“Carbocyclic rings” (formed with R² and R³) are saturated and contain 3to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl. This carbocyclic group being optionally substituted, e.g.,by halogen (e.g., chlorine, bromine, fluorine); cyano; lower alkoxy(e.g. methoxy, n-butoxy); nitro; amino; lower alkoxycarbonylamino (e.g.t-butoxycarbonylamino); lower alkanoylamino (e.g. acetylamino).

Heterocyclic rings (formed with R² and R³) refer to heterocyclic,saturated 3 to 6 membered rings containing one or two heteroatomsselected from nitrogen, oxygen and sulfur, e.g. aziridinyl, oxiranyl,thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl,dioxolanyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,pyrazolidinyl, etc. These rings may be further substituted, e.g. byt-butoxycarbonyl.

“Aryl” denotes phenyl or naphthyl groups which can optionally besubstituted e.g. by halogen (e.g. chlorine, bromine, fluorine); cyano;lover alkoxy (e.g. methoxy, n-butoxy); nitro; amino; loweralkoxycarbonylamino (e.g. t-butoxycarbonylamino); lower alkanoylamino(e.g. acetylamino).

“Heteroaryl” denotes 5- or 6-membered heteroaromatic groups whichcontain one or more rings and which have 5-9 carbon atoms and 1-4 heteroatoms, preferably N, O and/or S. Examples of such rings are for examplefuryl, pyranyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. These groupscan also be fused preferably to a phenyl ring, e.g. benzopyranyl,benzofuranyl, indolyl and quinolinyl. The “heteroaryl groups” areunsubstituted or substituted by halogen (e.g. chlorine, bromine,fluorine); cyano; lower alkoxy (e.g. methoxy, n-butoxy); nitro; amino;lower alkoxycarbonylamino (e.g. t-butoxycarbonylamino); loweralkanoylamino (e.g. acetylamino).

Preferred compounds of formula I are:

5-(4-Bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,

5-[(4-bromo-2′,3′,5′,6′-tetrahydro-8-methoxyspiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-yl)-methyl]-2,4-pyrimidinediamine,

5-(8-ethoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,

5-(4-chloro-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,

5-(8-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,

5-(8-methoxy-2,2-dimethyl-4-methylsulfanyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,

5-(8-ethoxy-2,2-dimethyl-4-propyl-2H-chromen6-ylmethyl)-pyrimidine-2,4-diamine,

5-[8-methoxy-4-(3-methoxy-prop-1-ynyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diamine,

5-[4-(4-fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diamine,

5-[(4-bromo-8-ethoxyspiro[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4-pyrimidinediamine,

5-(4-bromo-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine

and their pharmaceutically acceptable acid addition salts.

The compounds of formula I form pharmaceutically acceptable acidaddition salts with organic and inorganic acids. Examples of acidaddition salts of compounds of formula I are salts with mineral acids,for example hydrohalic acids such as hydrochloric acid, hydrogen bromideand hydrogen iodide, sulphuric acid, nitric acid, phosphoric acid andthe like, salts with organic sulphonic acids, for example with alkyl-and arylsulphonic acids such as methanesulphonic acid,p-toluenesulphonic acid, benzenesulphonic acid and the like as well assalts with organic carboxylic acids, for example with acetic acid,tartaric acid, maleic acid, citric acid, benzoic acid, salicyclic acid,ascorbic acid and the like.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be manufactured by methods known in the art,especially in accordance with the invention by

a) reacting a compound of the general formula

 in which R¹-R⁴ have the above significance, X represents a leavinggroup, and any functional group thereon being optionally protected,

with guanidine and cleaving off any protecting group present, or

b) for the manufacture of compounds of formula I in which R⁴ is otherthan hydrogen or halogen reacting a compound of the general formula

with a compound of the general formula

R⁴⁰Y  III

 in which R¹-R³ have the above significance, R⁴⁰ is as R⁴ excepthydrogen and halogen, any functional group in R¹-R³ and R⁴⁰ beingoptionally protected, one of the symbols X and Y represents a leavinggroup and the other represents a group which is eliminated with thisleaving group,

and cleaving off any protecting group present, or

c) converting a compound of formula I into a pharmaceutically acceptableacid addition salt.

The cyclization of the starting materials of formula II (where the ═CHXgroup can be either in (E)- or (Z)-configuration) with guanidine or asalt thereof in accordance with variant a) of the process in accordancewith the invention is preferably carried out in an inert organicsolvent, preferably in a lower alkanol, e.g. ethanol, or in dimethylsulphoxide, tetrahydrofuran or dioxan, and at about 50 to 100° C. Theguanidine is preferably used as a salt, e.g. as the hydrochloride, inwhich case the reaction is preferably carried out in the presence of abase, e.g. potassium t-butylate. In formula II the leaving group X ispreferably bromine, iodine, methylsulfonyloxy,trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy.

In the reaction of the compounds Ia and III in accordance with variantb) of the process in accordance with the invention there are to beunderstood under eliminating groups leaving groups X and, respectively,Y which react with one another and accordingly both “eliminate” with theformation of an eliminating byproduct. Many possibilities presentthemselves to a person skilled in the art in this respect; the followingembodiments are mentioned as examples:

X=bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy,phenylsulfonyloxy, p-tolylsulfonyloxy;

Y=(OH)₂B—.

This reaction with a boronic acid derivative III, also known as a“Suzuki coupling”, is preferably effected in an inert organic solventsuch as e.g. dioxane, tetrahydrofuran or dimethyl sulfoxide at atemperature between about 20° C. and the boiling point of the reactionmixture. A base such as an alkali metal carbonate, e.g. potassiumcarbonate, is preferably added as well as a catalyst, preferably apalladium complex such as tetrakis-(triphenylphosphine)-palladium.

A metal compound with Y=—Sn(lower-alkyl)₃, e.g. —Sn(CH₃ ₃ or—Sn(n-butyl)₃ (“Stille reaction”); —MgHal (“Grignard coupling”); or—ZnHal and Hal=bromine or iodine can be used in the above reaction asthe reaction partner III. No base is used in this reaction, although thecatalyst described above is preferably used. It can also be advantageousto add an inert salt, especially lithium chloride.

The aforementioned reaction can also be carried out with interchangedsubstituents X and Y, e.g. with X=—Sn(CH₃)₃, —MgHal or —ZnHal andY=bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy,phenylsulfonyloxy, p-tolylsulfonyloxy. The reaction conditions areessentially the same.

Functional groups, such as amino groups, should be protected. A suitableprotecting group for amino is e.g. t-butoxycarbonyl. Such group can besplit off (cf. Example 24) hydrolytically with acid treatment, e.g.trifluoroacetic acid, or mineral acid such as hydrochloric acid, in anorganic solvent e.g. methylene chloride or chloroform.

The manufacture of the acid addition salts of the compounds of formula Iin accordance with variant c) can be effected in a manner known per se,e.g. by reacting a compound of formula I with an equivalent amount ofthe desired acid, conveniently in a solvent such as water or in anorganic solvent such as ethanol, methanol or acetone. The temperature atwhich the salt formation is carried out is not critical. It generallylies at room temperature, but can also readily be lower or higher, forexample in the range of 0° C. to +50° C.

Compounds of formula I can be prepared by elaborating an aldehyde offormula IV optionally protected, according to known procedures byreacting it first with 3-anilinopropionitrile in the presence of a base,preferably KOtBu, and then heating the intermediate with an excess ofguanidine hydrochloride and base, preferably KOtBu, in ethanol.

a] If R⁴=aryl or heteroaryl

 the intermediate IV can be synthesized by coupling either free aldehydeIVa or a corresponding acetal V with an aryl- or heteroaryl boronic acid

 according to typical “Suzuki-conditions” (as in the above variant b) inan inert organic solvent like dimethylformamide, tetrahydrofuran,dioxane or dimethoxyethane at a temperature between 20° and the boilingpoint of the reaction mixture in the presence of a base, preferablyK₃PO₄ or Na₂CO₃, and a Pd-catalyst, preferably Pd(Ph₃P)₄.

A convenient variant generates the Suzuki-reagent in situ by reacting anaryl- or heteroaryl bromide or iodide with4,4,5,5,4′,4′,5′,5′-octamethyl[2,2′]bi[[1,3,2]dioxa-borolanyl] in thepresence of a Pd-catalyst, preferably PdCl₂(dppf), and KOAc in DMF(Tetrahedron Letters 1997, 3841).

b] If R⁴=alkynyl

 the intermediate IV can be synthesized by coupling either free aldehydeIVa or a corresponding acetal V with an alkyne according to typicalSonogashira-conditions, i.e. a Pd-catalyst, e.g. (Ph₃P)₂PdCl₂ orPd(Ph₃P)₄, a copper salt like CuI, and a base like triethylamine orpiperidine, without solvent or in an inert solvent likedimethylformamide.

c] If R⁴=alkyl, trialkylsilyl, alkylthio, or hydroxyalkyl

 the intermediate IV can be synthesized by subjecting compound V to ametal/halogen-exchange with nBuLi or tBuLi and reacting the resultantderivative VI with an electrophile, i.e. an alkyl halide, tosylate ortrifluoromethanesulfonate, a trialkylsilyl halide, a dialkyl disulfide,or an aldehyde or ketone.

d] If R⁴=Cl

 the intermediate IV can be synthesized by reacting the above preparedderivative VI with mesyl-Cl as electrophile, yielding, after cleavage ofthe acetal, the corresponding compound IV with R⁴=Cl.

Intermediate V is derived from intermediate IVa by treatment withMe₃OSiCH₂CH₂OSiMe₃ at −78° in CH₂Cl₂ and trifluoromethanesulphonic acidtrimethylsilyl ester as catalyst (Tetrahedron Letters 1980, 1357).

Intermediate IVa is synthesized from intermediate IVb by abromination-dehydro-bromination-sequence involving treatment with Br₂ inCH₂Cl₂ at −78° followed by DBN- or DBU-induced elimination of HBr in aninert solvent like tetrahydrofuran.

Aldehyde IVb is available by a Heck-type-reaction-ring closure accordingto literature precedents using iodo-phenol VII and vinyl-alcohol VIII inthe presence of a Pd-catalyst like Pd(POAc)₂ and a base like NaHCO₃ inan inert solvent like dimethylformamide (Tetrahedron Letters 1991,7739).

Iodo-phenol VII is available by iodination of IX according to standardconditions (N-iodo-succinimide in acetonitrile); the latter can beprepared by mono-alkylation of 3,4-dihydroxy-benzaldehyde X involvingdeprotonation with a base, preferably NaH in dimethylformamide, followedby reaction with an alkyl bromide or iodide.

The illustrative synthetic schemes follow below.

Building Up of the Ring System

wherein the symbols are as defined above.

Functionalization and Protection

Suzuki-coupling

The symbols are as defined above.

The above-mentioned procedure can be applied for the cleavage of thealdehyde protecting group of compounds 10-17.

Variants Involve a] Suzuki Coupling with Free Aldehyde or b] with InSitu Generated Pinacol-derived Boronic Ester

Functionalization Via Metal/Halogen-Exchange

Functionalization Via Sonogashira-coupling

Elaboration of the Final Product

the symbols used in the above schemata are as defined above.

The abbreviations have the meanings given below:

TMS=trimethylsilyl

TMSOTf=trifluoromethanesulphonic acid trimethylsilyl ester

DBN=1,5-diazabicyclo[4.3.0]non-5-ene

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

TPP=triphenylphosphin(yl)

DMF=dimethylformamide

Bu=butyl

R⁵-R⁹=alkyl

R¹⁰=alkyl, hydroxyalkyl, alkoxyalkyl, trialkylsilyloxyalkyl

DMSO=dimethylsulfoxide

Ph=phenyl

EtOH=ethanol

As mentioned earlier, the compounds of formula I and theirpharmaceutically acceptable salts possess valuable antibacterialproperties. They are active against a large number of pathogenicmicroorganisms such as e.g. Staphylococcus areus, Streptococcuspneumoniae etc. by virtue of their action in inhibiting bacterialdihydrofolate reductase (DHFR).

The inhibition of the enzyme was taken as a measurement for theantibacterial activity. It is determined using the method of Baccanariand Joyner (Biochemistry 20, 1710 (1981)); see also P. G. Hartman etal., FEB 242,157-160 (1988).

The IC₅₀ values (concentration at which the enzyme is inhibited to 50%)are determined graphically.

The following Table contains inhibitory concentrations determined in theabove test for representative members of the class of compound definedby formula I. The following microorganisms were tested:

Col. 1: MIC Spn1/1; μg/ml (Streptococcus pneumoniae 1/1, Trimethoprim-and Penicillin-resistant, Serotype 6; clinical isolate, stored at −80°C.)

 Lit.: H. Locher et al., Can. J. Infect. Dis.6: Suppl. C, p 469C.

Col. 2: MIC Sa101; μg/ml (Staphylococcus aureus 101, MRSA^(*))— andTrimethoprim-resistant; clinical isolate, stored at −80° C.)

 Lit.: A. Burdeska et al., FEBS 266:159-162, 1999; G. Dale et al., J.Mol. Biol. 266:23-30, 1997.

Col. 3: DHFR Spn1/1; μM—the IC₅₀-values in μM against the purified DHFRof the above strain Sp1/1 of Streptococcus pneumoniae.

Col. 4: DHFR Sa1; μM—the IC₅₀-values in μM against the purified DHFR ofthe strain 157/4696 (highly trimethoprim-resistant; clinical isolate) ofStaphylococcus aureus

 Lit.: A. Burdeska et al., FEBS 266:159-162, 1999; G. Dale et al., J.Mol. Biol. 266:23-30, 1997.

^(*)) MRSA=Methicillin Resistant Staphylococcus Aureus

TABLE MIC MIC Spn1/1 Sa101 DHFR Spn1/1 DHFR Sa1 Example No. μg/ml μg/mlμM μM  2 4 1 0.052 0.15 21 4 1 0.052 0.15  8 2 4 0.015 1.3  6 4 1 0.110.38  9 1 4 0.012 0.67  4 4 2 0.078 0.088 10 2 4 0.015 1.1 16 >8 4 0.680.22 32 >8 >8 0.19 0.08 30 4 2 0.0089 0.21  7 0.5 0.5 0.00033 0.11Trimethoprim >32 32 3.1 19 Epiroprim 4 16 0.19 2

The products in accordance with the invention can be used asmedicaments, e.g. in the form of pharmaceutical preparations for enteralor parenteral administration. The products in accordance with theinvention can be administered, for example, perorally, e.g. in the formof tablets, coated tablets, dragées, hard and soft gelatine capsules,solutions, emulsions or suspensions, rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.The invention thus also relates to a method of prophylaxis and treatmentof infectious diseases which comprises administering a compound offormula I alone or in combination with a sulphonamide.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the substances in accordance with the invention, if desired incombination with other therapeutically valuable substances, into agalenical administration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, the usual pharmaceutical adjuvants.

Not only inorganic carrier materials, but also organic carrier materialsare suitable as such carrier materials. Thus, lactose, corn starch orderivatives thereof, talc, stearic acid or its salts can be used, forexample, as carrier materials for tablets, coated tablets, dragées andhard gelatine capsules. Suitable carriers for soft gelatine capsulesare, for example, vegetable oils, waxes, fats and semi-solid and liquidpolyols (depending on the nature of the active substance no carriersare, however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and glucose. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols.

The usual preservatives, solubilizers, stabilizers, wetting agents,emulsifiers, sweeteners, flavorants, salts for varying the osmoticpressure, buffers, coating agents and antioxidants come intoconsideration as pharmaceutical adjuvants.

For parenteral administration the compounds of formula I and,respectively their salts are preferably provided as lyophilizates or drypowders for dilution with conventional carriers such as water orisotonic saline.

As already mentioned, the compounds of formula I and their salts haveantibacterial activity. They inhibit bacterial dihydrofolate reductaseand potentiate the antibacterial activity of sulphonamides such as e.g.sulfisoxazole, sulfadimethoxine, sulfamethoxazole,4-sulphanilamido-5,6-dimethoxy-pyrimidine,2-sulphanilamido-4,5-dimethyl-pyrimidine or sulfaquinoxaline,sulfadiazine, sulfamonomethoxine,2-sulphanilamido-4,5-dimethyl-isoxazole and other inhibitors of enzymeswhich are involved in folic acid biosynthesis, such as e.g. pteridinederivatives.

Oral, rectal and parenteral administration come into consideration forthe treatment of hosts, especially warm-blooded hosts, e.g., in humanmedicine, with the compounds of formula I or combinations thereof withsulphonamides. A daily dosage of about 0.2 g to about 2 g of a compoundof formula I in accordance with the invention comes into considerationfor adults. When administered in combination with antibacterialsulphonamides the ratio of compound I to sulphonamide can vary within awide range; it amounts to e.g. between 1:40 (parts by weight) and 1:1(parts by weight); 1:10 to 1:2 are preferred ratios. Thus, e.g. a tabletcan contain 80 mg of a compound I in accordance with the invention and400 mg of sulfamethoxazole, a tablet for children can contain 20 mg of acompound I in accordance with the invention and 100 mg ofsulfamethoxazole; syrup (per 5 ml) can contain 40 mg of compound I and200 mg of sulfamethoxazole.

The compounds of formula I are characterized by a high antibacterialactivity and, respectively, a pronounced synergistic effect incombination with sulphonamides and good tolerance.

The following Examples illustrate the invention. The temperatures aregiven in degrees Celsius.

EXAMPLE 1

a] 8-Methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

3.00 g of 5-iodo-vanilline (10.8 mmol), 3.63 g of NaHCO₃ (43.2 mmol),242 mg of Pd(OAc)2 (1.08 mmol), and 2.79 g of 2-methyl-but-3-en-2-ol(32.4 mmol) were mixed together under argon atmosphere in 21.5 ml ofabs. DMF (dimethylformamide) and heated for 2 hours to 120°. Thereaction mixture was cooled down to room temperature, poured ontocrushed ice, extracted twice with EtOEt (diethyl ether), washed withbrine, dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with n-hexane/AcOEt (ethyl acetate)=82/18) yielded1.16 g of the title compound as off-white solid, mp. 87-88°.

b] 4-Bromo-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

7.05 g of 8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (32.3 mmol)were dissolved in 110 ml of CH₂Cl₂ and cooled down to −78°. A solutionof 7.74 g of Br₂ (48.5 mmol) in 20 ml of CH₂Cl₂ was added dropwise andstirring continued for 45 min. Pouring onto crushed ice, twofoldextraction with ether, washing with brine, drying over magnesium sulfateand evaporation of the solvents left the corresponding trans-dibromidewhich was used crude for the next step.

The above prepared trans-dibromide was dissolved in 90 ml of abs. THF(tetra-hydrofuran) and treated at 0° with 11.9 g of DBN (96 mmol). Thereaction mixture was kept for 1 hour at room temperature and thenquenched by pouring onto crushed ice. Extraction with EtOEt, washingwith water and brine, drying over magnesium sulfate and evaporation ofthe solvents left a crude product which was purified by flashchromatography (SiO₂ with n-hexane/AcOEt=85/15) to yield 9.23 g of thetitle compound as white solid.

MS: (M)⁺ 296, 298, (M-CH₃)⁺ 281, 283.

c] 4-Bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene

477 mg of 4-bromo-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde(1.61 mmol) and 365 mg of 1,2-bis-(trimethylsilyloxy)ethane (1.77 mmol)were dissolved under argon atmosphere in 2 ml of abs. CH₂Cl₂ and cooleddown to −78°. 17.8 mg of trifluoromethanesulphonic acid trimethylsilylester (5 mol %) were added via syringe and the reaction allowed toproceed for 2 hours. The reaction was quenched by adding 32 μl ofpyridine before pouring the whole mixture onto crushed ice/NaHCO₃.Twofold extraction with ether, washing with water, drying over magnesiumsulfate and evaporation of the solvents left a crude product which waspurified by flash chromatography (SiO₂ with n-hexane/AcOEt=8/2) to yield366 mg of the title compound as a colourless oil, 97% pure according togas chromatography. Since the acetal is not perfectly stable on SiO₂, itis often advantageous to use the crude product for the following steps.

MS: (M)⁺ 340, 342, (M-CH₃)⁺ 325,327, (M-CH₃—C₂H₄O)⁺ 281, 283. NMR:(DMSO, 1H, δ, TMS) 1.40 (s, 6H), 3.78 (s, 3H), 3.9-4.0 (m, 2H), 4.0-4.1(m, 2H), 5.66 (s, 1H), 6.32 (s, 1H), 7.03 (2×br s, 2×1H).

d] 8-Methoxy-2,2,4-trimethyl-2H-chromene-6-carbaldehyde

360 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.06mmol) was dissolved in 4 ml of abs. THF and treated at −78° with 0.816ml of n-butyl lithium (1.5M, n-hexane, 1.2 eq.). 15 -min. later, 0.131ml of methyl iodide (2 eq.) were added via syringe and the cooling bathremoved after 10 min. After additional 30 min. the reaction mixture waspoured onto crushed ice/AcOEt, the organic layer washed with water andbrine, dried over magnesium sulfate and evaporated to dryness. The crudeproduct, 86% pure according to gas chromatography, was hydrolyzed asfollows:

The above prepared6-[1,3]dioxolan-2-yl-8-methoxy-2,2,4-trimethyl-2H-chromene was dissolvedin 3 ml of THF and treated with 1.5 ml of 3N HCl. After 30 min. at roomtemperature the reaction mixture was poured onto crushed ice/EtOEt, theorganic layer washed with water, dried over magnesium sulfate, andevaporated to dryness. Flash chromatography (SiO₂ withn-hexane/AcOEt=15/15) yielded 128 mg of the title compound as colourlessoil, 98% pure according to gas chromatography. Fractions containingsubstantial amounts of 8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehydewere discarded.

MS: (M)⁺ 232, (M-CH₃)⁺ 217. NMR: (DMSO, 1H, δ, TMS) 1.39 (s, 6H), 2.03(s, 3H), 3.83 (s, 3H), 5.67 (s, 1H), 7.37 (d, J=2, 1H), 7.44 (d,J=2,2H), 9.83 (s, 1H).

e]5-(8-Methoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine

To 125 mg of 8-methoxy-2,2,4-trimethyl-2H-chromene-6-carbaldehyde (0.54mmol), dissolved in 1.1 ml of abs. DMSO (dimethylsulphoxide) and 0.7 mlof t-butanol, were added 86.5 mg of 3-anilinopropionitrile (1.1 eq.) and72.5 mg of potassium t-butoxide (1.2 eq.), and the reaction was allowedto proceed for 2.5 hours at ambient temperature. Pouring onto crushedice, twofold extraction with AcOEt, washing with water and brine, dryingover magnesium sulfate and evaporation of the solvents left 194 mg ofcrude2-(8-methoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewhich was used as such.

The above prepared 194 mg of2-(8-methoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewere treated with 170 mg of guanidine hydrochloride (3.3 eq.), 199 mg ofpotassium t-butoxide (3.3 eq.) and 5 ml of ethanol and kept in an oilbath of 80° for 14 hours. The reaction mixture was then poured ontocrushed ice, extracted three times with AcOEt, washed with water andbrine, dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05), followed bycrystallisation from EtOEt, yielded 79 mg of the title compound aspale-yellow crystals, mp. 249-250°.

ISP MS: (M)⁺ 327.4. IR (cm⁻¹): 3458, 3447, 3098, 2970, 1656, 1638, 1596,1560, 1361, 1265, 1121, 1058, 791. NMR: (DMSO, 1H, δ, TMS) 1.31 (s, 6H),1.91 (s,3H), 3.50 (s,2H),3.70 (s,3H), 5.51 (s, 1H), 5.65 (br s, 2H),6.05 (br s,2H), 6.70 (d) J=2, 1H), 6.76 (d, J=2, 1H), 7.49 (s, 1H).

EXAMPLE 2

5-(4-Bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine

To 253 mg of 4-bromo-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde(0.81 mmol, see example 1b]), dissolved in 1.1 ml of abs. DMSO and 0.7ml of t-butanol were added 125 mg of 3-anilinopropionitrile (1.05 eq.)and 100 mg of potassium t-butoxide (1.1 eq.), and the reaction wasallowed to proceed for 3 hours at ambient temperature. Pouring ontocrushed ice, twofold extraction with AcOEt, washing with water andbrine, drying over magnesium sulfate and evaporation of the solventsleft 418 mg of crude2-(4-bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrileas yellow foam which was used as such.

The above prepared 418 mg of2-(4-bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewere treated with 248 mg of guanidine hydrochloride (3.3 eq.), 291 mg ofpotassium-t-butoxide (3.3 eq.) and 16 ml of ethanol and heated underreflux under argon atmosphere for 14 hours. After cooling, the reactionmixture was poured onto crushed ice, extracted twice with AcOEt, washedwith water and brine, dried over magnesium sulfate and evaporated todryness. Flash chromatography (SiO₂ with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05),followed by crystallization from EtOEt afforded 186 mg of the titlecompound as light-yellow crystals, mp.238-239°.

ISPMS: (MH)⁺ 391.2, 393.2, (M-Br)⁺ 311.2. IR (cm⁻¹): 3463, 3450, 3083,1657, 1638, 1596, 1560, 1465, 1352, 1143, 1097, 1000, 792, 732. NMR:(CDCl₃, 1H, δ, TMS) 1.48 (s, 6H), 3.65 (s, 2H), 3.79 (s, 3H), 4.54 (brs, 2H) 4.66 (br s, 2H), 6.02 (s, 1H), 6.62 (s, 1H). 6.92 (s, 1H), 7.80(s, 1H).

EXAMPLE 3

5-(4-Ethyl-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 1, but using in step d] ethyl iodideinstead of methyl iodide; yellow crystals of mp. 256-257°.

ISP MS: (MH)¹ 340.1, (M-CH₃)⁺ 325.2. IR (cm⁻¹): 3455, 3445, 3105, 2966,2934, 1654, 1636, 1595, 1558, 1464, 1360, 1122, 1041, 929, 791. NMR:(DMSO, 1H, δ, TMS) 1.04 (t, J=7.5, 3H), 1.31 (s, 6H), 2.31 (q, J=7.5,2H), 3.50 (s, 2H), 3.70 (s, 3H), 5.47 (s, 1H), 5.65 (br s, 2H), 6.05 (brs, 2H), 6.73 (s, 1H), 7.50 (s, 1H).

EXAMPLE 4

5-(8-Methoxy-2,2-dimethyl-4-methylsulfanyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 1, but using in step d] dimethyldisulfide as electrophile instead of methyl iodide; yellow solid.

ISP MS: (MH)⁺ 359.2. NMR: (DMSO, 1H, δ, TMS) 1.35 (s, 6H), 2.28 (s, 3H),3.53 (s, 2H), 3.72 (s, 3H), 5.44 (s, 1H), 5.68 (br s, 2H), 6.06 (br s,2H), 6.74 (s, 1H), 6.85 (s, 1H), 7.49 (s, 1H).

EXAMPLE 5

[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-methoxy-2,2-dimethyl-2H-chromen-4-yl]-methanolwas prepared in analogy to example 1, but using in step d]paraformaldehyde as electrophile giving4-hydroxymethyl-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehydeaccording to the following procedure as light-yellow crystals of mp.239-240°.

ISP MS: (MH)⁺ 343.3. NMR: (DMSO, 1H, δ, TMS) 1.34 (s, 6H), 3.48 (s, 2H),3.69 (s, 3H), 4.21 (d, J=5, 2H), 4.99 (t, J=5, 1H), 5.65 (br s, 2H),5.69 (s, 1H), 6.05 (br s, 2H), 6.69 (s, 1H), 6.74 (s, 1H), 7.48 (s, 1H).

4-Hydroxymethyl-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

360 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.06mmol) was dissolved in 3 ml of abs. THF and treated at −78° with 0.817ml of n-butyl lithium (1.55M, n-hexane, 1.2 eq.). 20 min. later 0.158 mgof paraformaldehyde (5 eq.) were added and the cooling bath removed.After 90 min. at ambient temperature, the reaction mixture was pouredonto crushed ice/AcOEt, the organic layer washed with water and brine,dried over magnesium sulfate, and evaporated to dryness to give a yellowoil which was hydrolyzed as follows:

The above prepared(6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromen-4-yl)-methanolwas dissolved in 3 ml of THF and treated at 0° with 1.5 ml of 3N HCl. 60min. later, the reaction mixture was poured onto crushed ice/AcOEt, theorganic layer washed with water and brine, dried over magnesium sulfateand evaporated to dryness. Flash chromatography (SiO₂ withn-hexane/AcOEt=1/1) afforded 123 mg of the title compound as colourless,viscous oil.

MS: (M)⁺ 248, (M-CH₃)⁺ 233.

EXAMPLE 6

5-(4-Chloro-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example. 2, but using4-chloro-8-methoxy-2;2dimethyl-2H-chromene-6-carbaldehyde instead of4-bromo-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde, yellowcrystals of mp. 221-222°. The starting compound was synthesized asdescribed below.

ISP MS: (MH)⁺ 347.4, 349.4. NMR: (DMSO, 1H, δ, TMS) 1.38 (s, 6H), 3.54(s, 2H), 3.73 (s, 3H), 5.68 (br s, 2H), 6.03 (s, 1H), 6.08 (br s, 2H),6.83 (d, J=2, 1H), 6.91 (d, J=2, 1H), 7.52 (s, 1H).

4-Chloro-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

366 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.07mmol) was dissolved in 4 ml of abs. THF and treated at −78° (dry-icebath) with 0.735 ml n-butyl lithium (1.6M, n-hexane, 1.1 eq.). 15 min.later, 0.114 ml of mesyl chloride (1.1 eq.) was added and the dry-icebath replaced by an ice-bth. After 30 min. the reaction mixture waspoured onto crushed ice/concentrated HCl and vigorously stirred tocleave the acetal. Twofold extraction with ether, washing with NaCl,drying over magnesium sulfate, and evaporation of the solvents left acrude product which was purified by flash chromatography (SiO₂ withn-hexane/AcOEt=87/13) to yield 77 mg of the title compound as whitecrystals.

MS: (M)⁺ 252, 254, (M-CH₃)⁺ 237, 239.

EXAMPLE 7

a] 8-Ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

23.28 g of 3-ethoxy-4-hydroxy-5-iodo-benzaldehyde (79.7 mmol), 16.74 gof NaHCO₃ (199.3 mmol), 1.789 g of Pd(OAc)2 (7.97 mmol) and 27.46 g of2-methyl-but-3-en-2-ol (318.8 mmol) were mixed together under argonatmosphere in 160 ml of abs. DMF and heated for 4¼ hours to 120°. Thereaction mixture was cooled down to room temperature, poured ontocrushed ice, extracted three times with AcOEt, washed with water, driedover magnesium sulfate and evaporated to dryness. Flash chromatography(SiO₂ with n-hexane/AcOEt=82/18) yielded 9.01 g of the title compound aswhite solid, 97% pure according to gas chromatography.

b] 4-Bromo-8-ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

5.00 g of 8-ethoxy-2,2-dimthyl-2H-chromene-6-carbaldehyde (21.5 mmol)was dissolved in 65 ml of methylene chloride and cooled down to −78°. Asolution of bromine in methylene chloride (26.6 ml 0.89M, 1.1 eq.) wasadded dropwise and stirring continued for 45 min. at −78° and for 1 hourat 0°. Pouring onto crushed ice, twofold extraction with ether, washingwith water, drying over magnesium sulfate and evaporation of thesolvents left the corresponding trans-dibromide which was used crude forthe next step.

The above prepared trans-dibromide was dissolved in 187 ml of abs. THFand treated at 0° with 8.02 g of DBN (64.6 mmol). The reaction mixturewas kept for 1¾ hours at room temperature and then quenched by pouringonto crushed ice. Extraction with EtOEt, washing with water, drying overmagnesium sulfate and evaporation of the solvents left a crude productwhich was purified by short flash chromatography (SiO2 withn-hexane/AcOEt=85/15) to yield 6.57 g of the title compound as whitesolid, >99% pure according to gas chromatography.

c]5-(4-Bromo-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine

To 212 mg of 4-bromo-8-ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde(0.68 mmol) dissolved in 1.1 ml of abs. DMSO and 0.7 ml of t-butanolwere added 104.6 mg of 3-anilinopropionitrile (1.05 eq.) and 84.1 mg ofpotassium t-butoxide (1.1 eq.), and the reaction was allowed to proceedfor 3 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water and brine, drying overmagnesium sulfate and evaporation of the solvents left 300 mg of crude2-(8-bromo-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrile,which was used as such.

The above prepared 300 mg of2-(8-bromo-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewere treated with 214 mg of guanidine hydrochloride (3.3 eq.), 252 mg ofpotassium t-butoxide (3.3 eq.) and 10 ml of ethanol and kept in an oilbath of 80° for 16 hours. The reaction mixture was then poured ontocrushed ice, extracted twice with AcOEt, washed with water and brine,dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05) yielded 87 mgof the title compound as pale-yellow crystals, mp. 218-219°.

ISP MS: (MH)⁺ 405.3, 407.3. NMR: (DMSO, 1H, δ, TMS) 1.28 (t, J=7,3H),1.37 (s, 6H), 3.53 (s, 2H), 4.00 (q, J=7, 2H), 5.68 (br s, 2H), 6.08 (brs, 2H), 6.25 (s, 1H), 6.80 (d, J=2, 1H), 6.88 (d, J=2, 1H), 7.51 (s,1H).

EXAMPLE 8

5-(8-Ethoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 1, but using in step d]4-bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene insteadof 4-bromo-6-[1,3] dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene;yellow solid of mp. 216-218°. The starting compound was synthesized asdescribed below.

ISP MS: (MH)⁺ 341.3. IR (cm⁻¹): 3451, 3325, 3106, 2922, 1634, 1596,1558, 1461, 1437, 1361, 1265, 1209, 1124, 1054, 997,793. NMR:(MSO, 1H,δ, TMS) 1.26 (t, J==7, 3H), 1.31 (s, 6H), 3.49 (s, 2H), 3.97 (q,J=7,2H), 5.51 (s, 1H), 5.65 (br s, 2H), 6.05 (br s, 2H), 6.70 (s, 1H),6.74 (s, 1H), 7.49 (s, 1H).

4-Bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene 6.57 g of4-bromo-8-ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (21.1 mmol) and5.667 g of 1,2-bis-(trimethylsilyloxy)ethane (27.5 mmol) were dissolvedunder argon atmosphere in 25 ml of abs. CH₂Cl₂ and cooled down to −78°.235 mg of trifluoromethanesulphonic acid trimethylsilyl ester (5 mol %)were added via syringe and the reaction allowed to proceed for 2 hours.The reaction was quenched by adding 418 μl of pyridine before pouringthe whole mixture onto crushed ice/NaHCO₃. Twofold extraction withether, washing with water and brine, drying over magnesium sulfate andevaporation of the solvents left, after high-vacuum-drying for 2 days)7.94 g of the title compound as off-white solid, 96.5% pure according togas chromatography. Since the acetal is not perfectly stable on SiO₂, itis generally used without further purification.

MS: (M)⁺ 354, 356, (M-CH₃)⁺ 339, 341.

EXAMPLE 9

5-(8-Ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 8, but using in step d] ethyl iodideinstead of methyl iodide as electrophile; yellow solid of mp. 222-225°(dec.).

ISP MS: (MH)⁺ 355.4. NMR: (DMSO, 1H, δ, TMS) 1.05 (t, J=7, 3H), 1.26 (t,J=7, 3H), 1.32 (s, 6H), 2.30 (q, J=7, 2H), 3.49 (s, 2H), 3.97 (q, J=7,2H), 5.48 (s, 1H), 6.65 (br s, 2H), 6.05 (br s, 2H), 6.73 (br s, 2H),7.49 (s, 1H).

EXAMPLE 10

5-(8-Ethoxy-2,2-dimethyl-4-propyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine was prepared in analogy to example 8, but usingin step d] 1-iodo-propane instead of methyl iodide as electrophile;yellow solid of mp. 208-209°. MS: (M)⁺ 368.3 (M-CH₃)⁺ 353.3.

EXAMPLE 11

5-(8-Ethoxy-4-isobutyl-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 8 as pale-yellow solid of mp. 188°.However, step d] was modified as follows:

8-Ethoxy-4-isobutyl-2,2-dimethyl-2H-chromene-6-carbaldehyde

311 mg of freshly purified4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (0.88mmol) were dissolved in 3.5 ml of abs. THF and treated at −78° with 2.0ml t-butyl lithium (1.5M, n-pentane, 3.4 eq.). 10 min. later, 0.805 mlof isobutyl iodide (5 eq.) were added via syringe and the cooling bathremoved after 10 min. After additional 60 min. the reaction mixture waspoured onto crushed ice/EtOEt, the organic layer washed with water,dried over magnesium sulfate and evaporated to dryness. The crudeproduct, containing according to gas chromatography 40% of desiredproduct and 57% of debromo-derivative, was hydrolyzed as follows:

The above prepared crude6-[1,3]dioxolan-2-yl-8-ethoxy-4-isobtyl-2,2-dimethyl-2H-chromene wasdissolved in 2.5 ml of THF and treated with 1.2 ml of 3N HCl. After 30min. at 0°, the reaction mixture was poured onto crushed ice/EtOEt, theorganic layer washed with water, dried over magnesium sulfate andevaporated to dryness. Flash chromatography (SiO₂ withn-hexane/AcOEt=9/1) yielded 83 mg of the title compound as colourlessoil, 98% pure according to gas chromatography.

MS: (M)⁺ 288.2 (M-CH₃)⁺ 273.2.

EXAMPLE 12

5-(8-Ethoxy-2,2-dimethyl-4-trimethylsilanyl-2H1-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 8, but using in step d]trimethylsilyl chloride instead of methyl iodide as electrophile; yellowsolid of mp. 189-190°.

MS: (M)⁺ 398.3 (M-CH₃)⁺ 383.2.

EXAMPLE 13

[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-methanolwas prepared in analogy to example 5, but starting the sequence with theethoxy-derivative; yellow solid of mp.187-189°.

ISP MS: (MH)⁺ 357.3.

EXAMPLE 14

a]8-Ethoxy-4-(3-hydroxy-prop-1-ynyl)-2,2-dimethyl-2H-chromene-6-carbaldehyde

To 351 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene (0.99mmol), dissolved in 1 ml of piperidine, were added successively 3.8 mg(0.02 eq.) of copper iodide, 5.2 mg (0.02 eq.) of triphenyl phosphineand 11.4 mg (0.01 eq.) of tetrakis-(triphenylphosphine)-palladium. Afterheating to 80° 463 mg (3.7 eq.) of propargyloxy-trimethylsilane wereadded within 2 hours in seven portions. 30 min. later the reactionmixture was cooled down and then poured onto crushed ice/HCl, vigorouslystirred for 10 min. to cleave the acetal, extracted twice with AcOEt,washed with water, dried over magnesium sulfate and evaporated todryness. Flash chromatography (SiO₂ with n-hexane/AcOEt 7/3) yielded 196mg of the title compound as colorless oil, 98% pure according to gaschromatography.

MS: (M)⁺ 286.1 (M-CH₃)⁺ 271.2.

b]3-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-prop-2-yn-1-ol

To 196 mg of8-ethoxy-4-(3-hydroxy-prop-1-ynyl)-2,2-dimethyl-2H-chromene-6-carbaldehyde(0.68 mmol) dissolved in 0.92 ml of abs. DMSO and 0.56 ml of t-butanolwere added 110 mg of 3-anilinopropionitrile (1.1 eq.) and 92 mg ofpotassium t-butoxide (1.2 eq.), and the reaction was allowed to proceedfor 3 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with brine, drying over magnesium sulfateand evaporation of the solvents left 273 mg of crude2-[8-ethoxy-4-(3-hydroxy-prop-1-ynyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-3-phenyl-amino-acrylonitrilewhich was used as such.

The above prepared 273 mg of2-[8-ethoxy-4-(3-hydroxy-prop-1-ynyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-3-phenyl-amino-acrylonitrilewere treated with 208 mg of guanidine hydrochloride (3.3 eq.), 244 mg ofpotassium t-butoxide (3.3 eq.), and 12 ml of EtOH and kept in an oilbath of 80° for 6½ hours. The reaction mixture was then poured ontocrushed ice, extracted twice with AcOEt, washed with water, dried overmagnesium sulfate and evaporated to dryness. Flash chromatography (SiO₂with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05) afforded after crystallisation fromEtOEt 58 mg of the title compound as pale-yellow crystals, mp. 242-244°.

ISP MS: (MH)⁺ 381.4. NMR: (DMSO, 1H, δ, TMS) 1.27 (t, J=7, 3H), 1.36 (s,6H), 3.51 (s, 2H), 3.98 (q, J=7, 2H), 4.28 (d, J=6,2H), 5.32 (t, J=6,1H), 5.67 (br s, 2H), 6.07 (s, 1H), 6.08 (br s, 2H), 6.79 (d, J=2, 1H),6.86 (d, J=2, 1H), 7.43 (s, 1H).

EXAMPLE 15

4-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-but-3-yn-2-olwas prepared in analogy to example 14, but using in step a]trimethyl-(1-methyl-prop-2-ynyloxy)-silane instead ofpropargyloxy-trimethylsilane as coupling partner; yellow crystals,mp.218-219°.

ISP MS: (MH)⁺ 395.3, (M—OH₂)⁺ 377.4. IR (cm^(−cm−1)): 3437, 3322, 2977,2927, 1638, 1596, 1592, 1457, 1436, 1359, 1265, 1209, 1137, 1095, 1061,998, 793.

EXAMPLE 16

5-[8-Methoxy-4-(3-methoxy-prop-1-ynyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 14, but using in step a] the methoxyinstead of the ethoxy-derivative as starting material and by methylationof the non-hydrolyzed intermediate propargylic alcohol as describedbelow; pale-yellow crystals, mp. 236-237°.

MS: (MH)⁺ 380.2, (M-CH₃)⁺ 365.2. NMR: (DMSO, 1H, δ, TMS) 1.36 (s, 6H),3.31 (s, 3H), 3.53 (s, 2H), 3.73 (s, 3H), 4.29 (s, 2H), 5.68 (br s, 2H),6.05 (br s, 2H), 6.12 (s, 1H), 6.78 (d, J=2, 1H), 6.86 (d, J=2, 1H),7.47 (s, 1H).

8-Methoxy-4-(3-methoxy-propyl-1-ynyl)-2,2-dimethyl-2H-chromene-6-carbaldehyde218 mg of 3-(6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromen-4-yl)-prop-2-yn-1-ol(0.69 mmol) was dissolved in 1.4 ml of abs. DMF and treated at 0° with43 mg of sodium hydride (ca. 50% in mineral oil, ca. 1.3 eq.).Deprotonation was allowed to proceed at ambient temperature for 0.2hours. The resultant solution of the corresponding sodium alkoxide wasthen treated at 0° with 0.112 ml of methyl iodide (2.6 eq.) and thenkept for 2 hours at room temperature. Careful hydrolysis with coldwater, extraction with EtOEt, washing with water and brine, drying overmagnesium sulfate and evaporation of the solvent left a crude product,which was hydrolyzed as follows:

It was dissolved in 3 ml of THF and treated with 1.5 ml of 3N HCl. After30 min. the mixture was poured onto crushed ice, extracted twice withAcOEt, washed with water and brine, dried over magnesium sulfate andevaporated to dryness. Purification of the residue by flashchromatography (silica gel with n-hexanetAcOEt=8/2) left finally 0.128 gof pure title compound as off-white gum, >98% pure according to gaschromatography.

EXAMPLE 17

a] 2-Cyclopropyl-8-ethoxy-8-methyl-2H-chromene-6-carbaldehyde

0.541 g of 3-ethoxy-4-hydroxy-5-iodo-benzaldehyde (1.85 mmol), 0.389 gof NaHCO₃ (4.63 mmol), 41.6 mg of Pd(OAc)2 (0.19 mmol) and 0.525 g of2-cyclopropyl-but-3-en-2-ol (4.31 mmol) were mixed together under argonatmosphere in 3.7 ml of abs. DMF and heated for 3½ hours to 120°. Thereaction mixture was cooled down to room temperature, poured ontocrushed ice, extracted twice with AcOEt, washed with water and brine,dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with n-hexane/AcOEt=82/18) yielded 298 mg of thetitle compound as light yellow oil.

MS: (MH)⁺ 258, (M-CH₃)⁺ 243.

b]5-(2-Cyclopropyl-8-ethoxy-2-methyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine

To 298 mg of 2-cyclopropyl-8-ethoxy-2-methyl-2H-chromene-6-carbaldehyde(1.15 mmol), dissolved in 1.5 ml of abs. DMSO and 1.0 ml of t-butanolwere added 185.5 mg of 3-anilinopropionitrile (1.1 eq.) and 155.3 mg ofpotassium t-butoxide (1.2 eq.), and the reaction was allowed to proceedfor 2.5 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water and brine, drying overmagnesium sulfate and evaporation of the solvents left 497 mg of crude2-(2-cyclopropyl-8-ethoxy-2-methyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewhich was used as such.

The above prepared 497 mg of2-(2-cyclopropyl-8-ethoxy-2-methyl-2H-chromen-6-ylmethyl)-3-phenylamino-acrylonitrilewere treated with 361 mg of guanidine hydrochloride (3.3 eq.), 424 mg ofpotassium t-butoxide (3.3 eq.), and 23 ml of ethanol and kept in an oilbath of 90° for 6½ hours. The reaction mixture was then poured ontocrushed ice, extracted twice with AcOEt, washed with water and brine,dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with CH₂Cl₂MeOH/25% NH₃=19/1/0.05), followed bycrystallization from EtOEt, delivered 175 mg of the title compound aspale-yellow crystals, mp. 195-196°.

ISP MS: (MH)⁺ 353.3. NMR: (DMSO, 1H, δ, TMS) 0.25-0.4 (m,4H), 1.11 (m,1H), 1.27 (t, J=7,3H), 1.35 (s, 3H), 3.45 (s, 2H), 3.98 (q, J=7, 2H),5.52 (d, J=10, 1H), 5.66 (br s, 2H), 6.01 (br s, 2H), 6.35 (d, J=10,1H), 6.46 (d, J=2, 1H), 6.72 (d, J=2, 1H), 7.47 (s, 1H).

EXAMPLE 18

5-(2-Cyclopropyl-8-mthoxy-2-methyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas pepared in analogy to example 17, but using in step a] the methoxy-instead of the ethoxy-derivative as starting material; light-yellowcrystals, mp. 218-219°. ISP MS: (MH)⁺ 339.3.

EXAMPLE 19

5-(8-Ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 1, but using in step e]8-ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (example 7a]) insteadof 8-methoxy-2,2,4-trimethyl-2H-chromene-6-carbaldehyde; yellowishcrystals of mp. 184-186°.

ISP MS: (MH)⁺ 327.3. NMR: (DMSO, 1H, δ, TMS) 1.27 (t, J=7,3H), 1.34 (s,3H), 3.46 (s, 2H), 3.98 (q, J=7, 2H), 5.66 (br s, 2H), 5.69 (d, J=9.5,1H), 6.02 (br s) 2H), 6.30 (d, J=9.5, 1H) 6.48 (d, J=2, 1H), 6.74 (d,J=2, 1H), 7.48 (s, 1H).

EXAMPLE 20

a]2′,3′,5′,6′-Tetrahydro-8-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehyde

1.07 g of 5-iodo-vanilline (3.85 mmol), 0.808 g of NaHCO₃ (9.62 mmol),86.4 mg of palladium diacetate (0.38 mmol), and 1.14 g of4-vinyl-tetrahydro-pyran-4-ol (8.89 mmol) were mixed together underargon atmosphere in 9 ml of abs. DMS and heated for 3.5 hours to 120°.The reaction mixture was cooled down to room temperature, poured ontocrushed ice, extracted twice with EtOEt, washed with water and brine)dried over magnesium sulfate and evaporated to dryness. Flashchromatography (SiO₂ with n-hexane/AcOEt=7/3) yielded 360 mg of thetitle compound as pale-yellow solid.

b]5-[(2′,3′,5′,6′-Tetrahydro-8-methocyspiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-yl)-methyl]-2,4-pyrimidinediamine

To 100 mg of2′,3′,5′,6′-tetrahydro-8-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehyde(0.485 mmol) dissolved in 1.5 ml of abs. DMSO and 1.0 ml of t-butanolwere added 78 mg of 3-anilinopropionitrile (1.1 eq.) and 65 mg ofpotassium t-butoxide (1.2 eq.), and the reaction was allowed to proceedfor 4.5 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water, drying over sodium sulfateand evaporation of the solvents left 120 mg of crude intermediate whichwas used as such.

The above prepared 120 mg of crude condensation product was treated with153 mg of guanidine hydrochloride (3.3 eq.), 180 mg of potassiumt-butoxide (3.3 eq.), and 8 ml of ethanol and kept in an oil bath of 800for 19 hours. The reaction mixture was then poured onto crushed ice,extracted twice with AcOEt, washed with water, dried over sodium sulfateand evaporated to dryness. Flash chromatography (SiO₂ withCH₂Cl₂/MeOH/25% NH₃=19//1/0.1), followed by crystalization from EtOEt,yielded 59 mg of the title compound as pale-yellow crystals.

ISP MS: (MH)⁺ 355.3. NMR: (DMSO, 1H, δ, TMS) 1.65-1.8 (m, 4H), 3.48 (s,2H), 3.63 (m, 2H), 3.73 (m, 2H), 3.75 (s, 3H), 5.67 (br s, 2H), 5.77 (d,J=10, 1H), 6.03 (br s, 2H), 6.40 (d, J=10, 1H), 6.50 (d, J=2, 1H), 6.80(d, J=2, 1H), 7.49 (s, 1H).

EXAMPLE 21

a]4-Bromo-2′,3′,5′,6′-tetrahydro-8-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehyde

0.360 g of2′,3′,5′,6′-tetrahydro-8-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehyde(1.38 mmol) (example 20a) were dissolved in 3.6 ml of CH₂Cl₂ and cooleddown to −78°. 6 ml of a 0.345M solution of bromine in methylene chloride(1.5 eq.) were added dropwise, and stirring continues for 90 min.Pouring onto crushed ice, twofold extraction with ether, washing withwater and brine, drying over magnesium sulfate and evaporation of thesolvents left 430 mg of the corresponding trans-dibromide as colourlesssolid which was used crude for the next step.

The above prepared trans-dibromide was dissolved in 10 ml of abs. THFand treated at 0° with 0.509 g of DBN (4 eq.). The reaction mixture waskept for 2 hours at room temperature and then quenched by pouring ontocrushed ice. Extraction with EtOEt, washing with water and brine, dryingover magnesium sulfate and evaporation of the solvents left a crudeproduct which was purified by flash chromatography (SiO₂ withn-hexane/AcOEt=8/2) to yield 0.185 g of the title compound as whitesolid, mp. 107-108°.

MS: (M)⁺ 338, 340, (M—COH)⁺ 309, 311.

b]5-[(4-Bromo-2′,3′,5′,6′-tetrahydro-8-methoxyspiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-yl)-methyl]-2,4-pyrimidinediamine

To 121 mg of4-bromo-2′,3′,5′,6′-tetrahydro-8-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehyde(0.36 mmol) dissolved in 1.5 ml of abs. DMSO and 1.0 ml of butanol wereadded 54.8 mg of 3-anilinopropionitrile (1.5 eq.) and 44 mg of potassiumt-butoxide (1.1 eq.), and the reaction was allowed to proceed for 3hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water, drying over magnesium sulfateand evaporation of the solvents left 170 mg of crude product which wasused as such.

The above prepared 170 mg were treated with 115 mg of guanidinehydrochloride (3.3 eq.), 147 mg of potassium t-butoxide (3.3 eq.), and 8ml of ethanol and kept in an oil bath of 80° for 14 hours. The reactionmixture was then poured onto crushed ice, extracted twice with AcOEt,washed with water and brine, dried over magnesium sulfate and evaporatedto dryness. Flash chromatography (SiO₂ with CH₂Cl₂/MeOH/25%NH₃=19/1/0.05) yielded 46 mg of the title compound as pale-yellowcrystals, mp. 232-233°.

ISP MS: (MH)⁺ 433.4, 435.4. NMR: (DMSO) 1H, δ, TMS) 1.7-1.8 (m,4H),3.55(s,2H),3.6-3.75 (m,4H),3.77 (s, 3H), 5.68 (br s, 2H), 6.09 (br s, 2H),6.33 (s, 1H), 6.80 (d, J=2, 1H), 6.95 (d, J=2, 1H), 7.52 (s, 1H).

EXAMPLE 22

4-Bromo-6-[(2,4-diamino-5-pyrimidinyl)methyl]-8-methoxy-spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylicacid 1,1-dimethylethyl ester was prepared in analogy to example 21, butusing in step a]6-formyl-8-methoxy-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester instead of2′,3′,5′,6′-tetrahydro-methoxy-spiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-carboxaldehydeas starting material; light-yellow crystals, mp. 2360. The startingcompound was prepared as described in example 20, but using in step a]4-hydroxy-4-vinyl-piperidine-1-carboxylic acid 1,1-dimethyl-ethyl esterinstead of 4-vinyl-tetrahydro-pyran-4-ol.

ISP MS: (MH)⁺ 532.3, 534.3. NMR: (DMSO, 1H, δ, TMS) 1.40 (s, 9H),1.6-1.7 (m, 2H), 1.8-1.85 (m, 2H), 3.16 (br s, 2H), 3.55 (s, 2H), 3.70(m, 2H), 3.76 (s, 3H), 5.69 (br s,2H), 6.10 (br s, 2H), 6.29 (s, 1H),6.80 (d, J=2, 1H), 6.95 (d, J=2, 11H), 7.52 (s, 1H).

EXAMPLE 23

4-Bromo-6-[(2,4-diamino-5-pyrimidinyl)methyl]-8-ethoxy-spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylic acid 1,1-dimethylethylester was prepared in analogy to example 22, but starting the wholereaction sequence with 3-ethoxy-4-hydroxy-5-iodo-benzaldehyde instead of5-iodo-vanilline; orange crystals, mp. 235-236° (dec.).

ISP MS: (MH)⁺ 546.1, 548.1. NMR: (DMSO, 1H, δ, TMS) 1.30 (t, J=7, 3H),1.40 (s, 9H), 1.6-1.7 (m, 2H), 1.75-1.85 (m, 2H), 3.05-3.25 (m, 2H),3.54 (s, 2Hi), 3.72 (m, 2H), 4.01 (q, J=7, 2H), 5.68 (br s, 2H), 6.09(br s, 2H), 6.28 (s, 1H), 6.80 (s, 1H), 6.92 (s, 1H), 7.52 (s, 1H).

EXAMPLE 24

5-[(4-Bromo-8-methoxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl)methyl]-2,4-pyrimidinediamine

155 mg of4-bromo-6-[(2,4-diamino-5-pyrimidinyl)methyl]-8-methoxy-spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylicacid 1,1-dimethylethyl ester (0.29 mmol, example 22) was dissolved in 3ml of abs. methylene chloride, treated with 0.60 ml of trifluoroaceticacid, and the reaction was allowed to proceed for 1.5 hours at ambienttemperature. Evaporation of the solvents, followed by flashchromatography (SiO₂ with CH₂Cl₂/MeOH/25% NH₃=90/10/1) yielded 125 mg ofthe title compound as pale-yellow crystals, mp. >2700.

ISP MS: (MH)⁺ 432.4, 434.4. NMR: (DMSO, 1H, δ, TMS) 1.6-1.7 (m, 2H),1.75-1.8 (m, 2H), 2.7-2.8 (m, 2H), 2.8-2.9 (m, H), 3.55 (s, 2H), 3.76(s, 3H), 5.68 (br s, 2H), 6.08 (br s, 2H), 6.30 (s, 1H), 6.79 (d, J=2,1H), 6.93 (d, J=2, 1H), 7.52 (s, 1H).

EXAMPLE 25

6-[(2,4-Diamino-5-pyrimidinyl)methyl]-8-ethoxy-4-(3-hydroxy-1-butynyl)spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylicacid 1,1-dimethylethyl ester was prepared in analogy to examples 15 and22 as light-yellow solid, mp.141-143°.

ISP MS: (MH⁺ 536.3. IR (cm⁻¹): 3469, 3355, 2925, 2854, 1688, 1623, 1565,1461, 1424, 1366, 1262, 1244, 1157, 1110, 1066, 1032, 972, 868.

EXAMPLE 26

6-[(2,4-Diamino-5-pyrimidinyl)methyl]-8-methoxy-spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylicacid 1,1-dimethylethyl ester was prepared in analogy to example 22, butomitting the bromination/dehydro-bromination-sequence; pale-yellowcrystals, mp. 192-193°.

ISP MS: (MH)⁺ 454.5.

EXAMPLE 27

5-[(8-methoxyspiro[2H-1-benzopyran-2,4′-piperidine]-6-yl)methyl]-2,4-pyrimidine-diaminewas prepared in analogy to example 24, but using the product of example26 as starting material; yellow crystals.

ISP MS: (MH)⁺ 354.4.

EXAMPLE 28

6-[(2,4-Diamino-5-pyrimidinyl)methyl]-ethoxy-spiro[2H]-1-benzopyran-2,4′-piperidine-1′-carboxylicacid 1,1-dimethylethyl ester was prepared in analogy to example 26, butusing the ethoxy- instead of the methoxy-intermediate; yellow crystals,mp. 209-212° (dec.).

ISP MS: (MH)⁺ 468.3.

EXAMPLE 29

a] 8-Methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-6-carboxaldehyde

1.444 g of 5-iodo-vanilline (5.19 mmol), 1.745 g of NaHCO₃ (20.8 mmol),117 mg of palladium diacetate (0.52 mmol) and 1.019 g of1-vinyl-cyclobutanol (10.4 mmol) were mixed together in an argonatmosphere in 14 ml of abs. DMF and heated for 3.5 hours to 120°. Thereaction mixture was cooled to room temperature, poured onto crushedice, extracted twice with EtOEt, washed with water and brine, dried overmagnesium sulfate and evaporated to dryness. Flash chromatography (SiO₂with n-hexane/AcOEt=8/2) yielded 0.137 g of the title compound aspale-yellow oil.

b]4-Bromo-8-methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-6-carboxaldehydewas prepared from the product of example 29a] as described in example1b]; off-white crystals, mp. 128-129°.

MS: (M)⁺ 308.1, 310.1 (M—CO)⁺ 280.0, 282.0. NMR: (DMSO, 1H, δ, TMS)1.7-1.9 (m, 2H), 2.25-2.35 (m, 2H), 2.35-2.45 (m, 2H), 3.88 (s, 3H),6.83 (s, 1H), 7.49 (d, J=1, 1H), 7.53 (d, J=2, 1H), 9.87 (s, 1H).

c]5-[(4-Bromo-8-methoxyspiro[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4-pyrimidinediamine

To 94 mg of4-bromo-8-methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-6-carboxaldehyde(0.30 mmol) dissolved in 1.2 ml of abs. DMSO and 0.8 ml of t-butanolwere added 46.7 mg of 3-anilinopropionitrile (1.05 eq.) and 37.5 mg ofpotassium t-butoxide (1.1 eq.), and the reaction was allowed to proceedfor 2.5 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water and brine, drying overmagnesium sulfate and evaporation of the solvents left 133 mg of crudeproduct which was used as such.

The above prepared 133 mg of crude condensation product was treated with95.8 mg of guanidine hydrochloride (3.3 eq.), 112.6 mg of potassiumt-butoxide (3.3 eq.), and 4.5 ml of ethanol and kept in an oil bath of80° for 6 hours. The reaction mixture was then poured onto crushed ice,extracted twice with AcOEt, washed with brine, dried over magnesiumsulfate and evaporated to dryness. Flash chromatography (SiO₂ withCH₂Cl₂/MeOH/25% NH₃=19/1/0.05) followed by crystallization from EtOEtyielded 54 mg of the title compound as pale-yellow crystals,mp.231-232°.

ISP MS: (MH)⁺ 403.3, 405.3. NMR: (DMSO, 1H, δ, TMS) 1.7-1.85 (m, 2H),2.18-2.25 (m, 2H), 2.27-2.38 (m, 2H), 3.54 (s, 2H), 3.76 (s, 3H), 5.68(br s, 2H), 6.08 (br s, 2H), 6.65 (s, 1H), 6.77 (d, J=2, 1H), 6.91 (d,J=2, 1H), 7.52 (s, 1H).

EXAMPLE 30

5-[(4-Bromo-8-ethoxyspiro[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4-pyrimidinediaminewas prepared in analogy to example 29, but using the ethoxy- instead ofthe methoxy-intermediate; yellow crystals, mp. 213-214°.

ISP MS: (MH)⁺ 417.2, 419.2.

EXAMPLE 31

5-[(8-Methoxyspiro[2H-1-benzopyran-2,1′-cyclohexan]-6-yl)methyl]-2,4-pyrimidine-diamineas prepared in analogy to example 17, but starting with 5-iodo-vanillineand 1-vinyl-cyclohexanol; yellow crystals, mp. 181-182°.

ISP MS: (MH)⁺ 353.3.

EXAMPLE 32

a] 4-(4-Fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde

235 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (0.689mmol) (example 1c), 145 mg of 4-fluorophenyl boronic acid (1.5 eq.), and39.8 mg of tetrakis-triphenylphosphine-palladium (0.05 eq.) were mixedtogether in an argon atmosphere in 3 ml of abs. DMF and 1.5 ml of 2MK₃PO₄ and heated for 2 hours to 80°. The reaction mixture was cooled toroom temperature, poured onto crushed ice/conc. HCl/AcOEt and vigorouslystirred to cleave the acetal. Separation of the layers, washing theaqueous phase with water, drying over sodium sulfate and evaporation ofthe solvents yielded 500 mg crude product. Flash chromatography (SiO₂with n-hexane/AcOEt=8/2) gave 199 mg of the title compound as colourlessgum.

MS: (M)⁺ 312.1, (M-CH₃)⁺ 297.1.

b]5-[4-(4-Fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diamine

To 194 mg of4-(4-fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde(0.621 mmol) dissolved in 2 ml of abs. DMSO and 1.3 ml of t-butanol wereadded 100 mg of 3-anilinopropionitrile (1.1 eq.) and 84 mg of potassiumt-butoxide (1.2 eq.), and the reaction was allowed to proceed for 4hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with water, drying over sodium sulfateand evaporation of the solvents left crude2-[4-(4-fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-3-phenylamino-acrylonitrilewhich was used as such.

The above prepared crude2-[4-(4-fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-3-phenylaminoacrylonitrilewas treated with 196 mg of guanidine hydrochloride (3.3 eq.), 230 mg ofpotassium t-butoxide (3.3 eq.) and 14 ml of ethanol and kept in an oilbath of 80° for 14 hours. The reaction mixture was then poured ontocrushed ice, extracted twice with AcOEt, washed with water, dried oversodium sulfate and evaporated to dryness. Flash chromatography (SiO₂with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05) followed by crystallization fromEtOEt/n-hexane yielded 21 mg of the title compound as pale-yellowcrystals, mp. 265° dec.

ISP MS: (MH)⁺ 407.4. NMR: (DMSO, 1H, δ, TMS) 1.40 (s, 6H), 3.45 (s, 2H),3.74 (s, 3H), 5.66 (br s,2H), 5.73 (s, 1H),6.03 (br s, 2H),6.42 (d, J=2,1H),6.81 (d, J=2,1H),7.22 (t, J=9, 2H),7.32 (m,2H), 7.40 (s, 1H).

EXAMPLE 33

5-[4-(3-Fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 32 but using 3-fluorophenyl boronicacid instead of the 4-F-derivative; pale-yellow crystals, mp. 267° dec.

MS: (M)⁺ 406.1, (M-CH₃)⁺ 391.1.

EXAMPLE 34

5-[8-Ethoxy-4-(3-fluoro-phenyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 33 but using the ethoxy- instead ofthe methoxy-intermediate; yellow crystals, mp. 185-186°.

ISP MS: (MH)⁺ 421.4.

EXAMPLE 35

5-[8-Ethoxy-4-(4-fluoro-phenyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 34 but using 4-fluorophenyl boronicacid instead of the 3-F-derivative; pale-yellow crystals, mp. 204-205°dec.

MS: (M)⁺ 420.2, (M-CH₃)⁺ 405.2. IR (cm⁻¹): 3454, 3433, 2976, 1642, 1624,1556, 1453, 1433, 1355, 1264, 1217, 1141, 1071, 958, 819, 792.

EXAMPLE 36

5-(8-Ethoxy-2,2-dimethyl-4-thiophen-2-yl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 35 but using 2-thiophene boronic acidinstead of 4-fluorophenyl boronic acid; yellow crystals, mp. 213-214°dec.

MS: (M)⁺ 408.2, (M-CH₃ ⁺ 393.1. NMR: (DMSO, 1H, δ, TMS) 1.30 (t, J=7,3H), 1.39 (s, 6H), 3.49 (s, 2H), 4.02 (q, J=7, 2H), 5.65 (br s, 2H),5.90 (s, 1H), 6.04 (br s, 2H), 6.81 (d, J=2, 1H), 6.83 (d, J=2, 1H),7.10 (m, 2H), 7.45 (s, 1H), 7.53 (m, 1H).

EXAMPLE 37

5-(8-Ethoxy-2,2-dimethyl-4-thiophen-3-yl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 36 but using 3-thiophene boronic acidinstead of the 2-substituted analogue; yellow crystals, mp. 217° dec.

MS: (M)⁺ 408.2, (M-CH₃)⁺ 393.2. IR (cm⁻¹): 3455, 3431, 2923, 2853, 1648,1630, 1557, 1466, 1264, 1217, 1139, 1072, 937, 840, 792.

EXAMPLE 38

a] 4-(8-Ethoxy-6-formyl-2,2-dimethyl-2H-chromen-4-yl)-benzonitrile

250 mg of 4-bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene(0.700 mmol), 241 mg of 4-cyanophenyl boronic acid (1.5 eq.), and 40.7mg of tetrakis-triphenylphosphine-palladium (0.05 eq.) were mixedtogether in an argon atmosphere in 3.2 ml abs. DMF and 1.6 ml of 2MK₃PO₄ and heated for 1.5 hours to 800. The reaction mixture was cooledto room temperature, poured onto crushed ice/conc. HCl/EtOEt andvigorously stirred to cleave the acetal. Separation of the layers,washing the organic phase with water, drying over sodium sulfate andevaporation of the solvents, followed by flash chromatography (SiO₂ withn-hexane/AcOEt=8/2) yielded 244 mg of the title compound as off-whitefoam.

MS: (M)⁺ 333.2, (M-CH₃)⁺ 318.2.

b]4-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-benzonitrile

To 235 mg of4-(8-ethoxy-6-formyl-2,2-dimethyl-2H-chromen-4-yl)-benzonitrile (0.700mmol) dissolved in 0.94 ml of abs. DMSO and 0.56 ml of t-butanol wereadded 113.2 mg of 3-anilinopropionitrile (1.1 eq.) and 94.8 mg ofpotassium t-butoxide (1.2 eq.), and the reaction was allowed to proceedfor 2.5 hours at ambient temperature. Pouring onto crushed ice, twofoldextraction with AcOEt, washing with brine, drying over sodium sulfateand evaporation of the solvents left 325 mg of crude4-[6-(2-cyano-3-phenylamino-allyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-benzonitrile,which was used as such.

The above prepared crude4-[6-(2-cyano-3-phenylamino-allyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-benzonitrilewas treated with 222 mg of guanidine hydrochloride (3.3 eq.), 261 mg ofpotassium t-butoxide (3.3 eq.), and 13 ml of ethanol and kept in an oilbath of 80° for 15 hours. The reaction mixture was then poured ontocrushed ice, extracted twice with AcOEt, washed with brine, dried oversodium sulfate and evaporated to dryness. Flash chromatography (SiO₂with CH₂Cl₂/MeOH/25% NH₃=19/1/0.05) followed by crystallization fromEtOEt yielded 110 mg of the title compound as yellow crystals, mp.219-220° dec.

ISP MS: (MH)⁺ 428.5. NMR: (DMSO, 1H, δ, TMS) 1.30 (t, J=7,3H), 1.41 (s,6H), 3.43 (s, 2H), 4.02 (q, J=7, 2H), 5.65 (br s, 2H), 5.88 (s, 1H),6.03 (br s, 2H), 6.42 (d, J=2, 1H), 6.80 (d, J=2, 1H), 7.42 (s, 1H),7.48 (d, J=8, 2H), 7.86 (d, J=8, 1H).

EXAMPLE 39

5-[(4-(4-Cyano-phenyl)-8-methoxyspiro[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4-pyrimidinediamine was prepared inanalogy to example 38, but using in step a]4-bromo-8-methoxy-spiro[2H-1-benzopyran-2,1′-cyclobutane]-6-carboxaldehyde(prepared in example 29b) instead of4-bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene ascoupling partner; yellow crystals, mp. 214-215° dec.

ISP MS: (MH)⁺ 426.4, (M—C₂H_(4T))⁺ 398.3. NMR: (DMSO, 1H, δ, TMS)1.7-1.85 (m, 2H), 2.19-2.28 (m, 2H), 2.30-2.40 (m, 2H), 3.44 (s, 2H),3.77 (s, 3H), 5.65 (br s, 2H), 6.04 (br s, 2H), 6.28 (s, 1H), 6.41 (d,J=2, 1H), 6.83 (d, J=2, 1H), 7.43 (s, 1H), 7.53 (d, J=8.5, 2H), 7.88 (d,J=8.5, 2H).

EXAMPLE 40

a]8-Ethoxy-6-formyl-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester

0.514 g of 3-ethoxy-4-hydroxy-5-iodo-benzaldehyde (1.76 mmol), 0.537 gof NaHCO₃ (4.40 mmol), 39.5 mg of palladium diacetate (0.18 mmol), and0.500 g of 4-hydroxy-4-vinyl-piperidine-1-carboxylic acid1,1-dimethyl-ethyl ester (2.20 mmol) were mixed together under argonatmosphere in 4.8 ml of abs. DMF and heated for 5.5 hours to 120°. Thereaction mixture was cooled down to room temperature, poured ontocrushed ice, extracted twice with AcOEt, washed with brine, dried overmagnesium sulfate and evaporated to dryness. Flash chromatography (SiO₂with n-hexane/AcOEt=8/2) yielded 189 mg of the title compound aspale-yellow oil.

ISP MS: (MNa)⁺ 396.3, (MH)⁺ 374.4.

b]4-Bromo-8-ethoxy-6-formyl-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester was prepared from the product of example 40a] as described in example 1 b]; off-white crystals, mp. 148-150°.

ISP MS: (MNa)⁺ 474.2, 476.2, (MH)⁺ 452.4, 454.4.

c]4-Bromo-6-(1,3-dioxolan-2-yl)-8-ethoxy-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester was prepared from the above compound ofexample 40 b] as described in example 1 c]; white foam.

ISP MS: (MNa)⁺ 518.1, 520.1, (MH)⁺ 496.1, 498.1.

d]4-(4-Cyanophenyl)-8-ethoxy-6-formyl-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester

250 mg of4-bromo-6-(1,3-dioxolan-2-yl)-8-ethoxy-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester (0.500 mmol), 150 mg of4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.3 eq.),and 29.1 mg of tetrakis-(triphenylphosphine)-palladium (0.05 eq.) weremixed together under argon atmosphere in 2.3 ml of abs. DMF and 1.15 mlof 2M K₃PO₄ and heated for 2 hours to 80°. The reaction mixture wascooled to room temperature, poured onto crushed ice/conc. HCl/AcOEt, andvigorously stirred for 2 hours to cleave the acetal. Separation of thelayers, washing the organic phase with brine, drying over sodium sulfateand evaporation of the solvents, followed by flash chromatography (SiO₂with n-hexane/AcOEt=8/2) afforded 214 mg of the title compound asoff-white solid.

ISP MS: (MNa)⁺ 497.2, (MH)⁺ 475.3.

c]4-(4-Cyanophenyl)-6-[(2,4-diamino-5-pyrimidinyl)methyl]-8-ethoxy-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester

To 210 mg of4-(4-cyanophenyl)-8-ethoxy-6-formyl-spiro[2H-1-benzopyran-2,4′-piperidine]-1′-carboxylicacid 1,1-dimethylethyl ester (0.44 mmol) dissolved in 0.59 ml of abs.DMSO and 0.35 ml of t-butanol were added 71.2 mg of3-anilinopropionitrile (1.1 eq.) and 59.6 mg of potassium t-butoxide(1.2 eq.), and the reaction was allowed to proceed for 3.75 hours atambient temperature. Pouring onto crushed ice, twofold extraction withAcOEt, washing with brine, drying over sodium sulfate and evaporation ofthe solvents left 325 mg of crude product which was used as such.

The above prepared crude condensation product was treated with 144 mg ofguanidine hydrochloride (3.3 eq.), 164 mg of potassium t-butoxide (3.3eq.), and 8 ml of ethanol and kept in an oil bath of 80° for 14 hours.The reaction mixture was then poured onto crushed ice, extracted twicewith AcOEt, washed with brine, dried over sodium sulfate and evaporatedto dryness. Flash chromatography (SiO₂ with CH₂Cl₂/MeOH/25%NH₃=19/1/0.05) followed by crystallization from EtOEt, yielded 48 mg ofthe title compound as yellow crystals, mp. 241-243° dec.

ISP MS: (MH)⁺ 569.2. NMR: (DMSO, 1H, δ, TMS) 1.31 (t, 3H), 1.41 (s, 9H),1.6-1.7 (m,2H), 1.78-1.9 (m, 2H), 3.15-3.3 (m, 2H), 3.44 (s, 2H), 3.72(m, 2H), 4.02 (m),2H), 5.65 (br s, 2H), 5.93 (s, 1H), 6.05 (br s, 2H),6.44 (s, 1H), 6.84 (s, 1H), 7.44 (s, 1H), 7.51 (d, J=7, 2H), 7.86 (d,J=7, 2H).

EXAMPLE 41

5-(8-Cyclopropylmethoxy-2,2-dimethoxy-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 1, but using in step e]8-cyclopropylmethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde as couplingpartner; pale-yellow crystals, mp. 204-206°.

ISP MS: (MH)⁺ 353.3. NMR: (CDCl₃, 1H, δ, TMS) 0.32 (m),2H), 0.57 (m,2H), 1.25 (m, 1H), 1.45 (s, 6H), 3.58 (s, 2H), 3.81 (d, J=7, 2H), 4.50(br s, 2h), 4.62 (br s, 2H), 5.61 (d, J=10, 1H), 6.23 (d, J=10, 1H),6.46 (d, J=2, 1H), 6.62 (d, J=2, 1H), 7.78 (s, 1H).

EXAMPLE 42

5-(8-Methoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine was prepared in analogy to example 32, but usingin step a] phenylboronic acid; yellow crystals, mp. >260°.

MS: (M)⁺ 388, (M-CH₃)⁺ 373.

EXAMPLE 43

2-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-propan-2-olwas obtained as yellow crystals, mp. 209-210°.

ISP MS: (MH)⁺ 385.4. NMR: (DMSO, 1H, δ, TMS) 1.26 (t, J=7, 3H), 1.31(s,6H), 1.36 (s, 6H), 3.48 (s, 2H), 3.96 (q, J=7, 2H), 4.82 (s, 1H),5.63 (br s, 2H), 5.71 (s, 1H), 6.03 (br s, 2H), 6.72 (d, J=2, 1H), 7.36(d, J=2, 1H), 7.43 (s, 1H).

This product was prepared in analogy to example 8, but using acetoneinstead of methyl iodide as electrophile yielding8-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-2H-chromene-6-carbaldehydeaccording to the following experimental procedure:

8-Ethoxy-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-2H-chromene-6-carbaldehyde

385 mg of 4-bromo-6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromene (1.08 mmol) weredissolved in 9 ml of abs. THF and treated at −78° with 0.867 ml ofn-butyl lithium (1.5M, n-hexane, 1.2 eq.). 15 min. later 0.239 ml ofacetone (3 eq.) dissolved in 2 ml of abs. THF were added and the coolingbath removed after 10 min. After additional 20 min. the reaction mixturewas poured onto crushed ice/AcOEt, the organic layer washed with waterand brine, dried over magnesium sulfate and evaporated to dryness. Thecrude product was hydrolyzed as follows:

The above prepared2-(6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl)-propan-2-olwas dissolved in 6 ml of methanol and 3 ml of water and treated with 54mg of pyridinium p-toluenesulfonate. After 15 min. at room temperature,the reaction mixture was poured onto crushed ice/AcOEt, the organiclayer washed with water, dried over magnesium sulfate and evaporated todryness. Flash chromatography (SiO₂ with n-hexane/AcOEt=7/3) yielded 194mg of the title compound as colourless oil.

MS: (M)⁺ 290, (M-CH₃)⁺ 275.

EXAMPLE 44

2-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-butan-2-olwas prepared in analogy to example 43 but using 2-butanone aselectrophile instead of acetone; beige crystals, mp. 127-128°.

ISP MS: (MH)⁺ 399.5.

EXAMPLE 45

5-(8-Ethoxy-4-isopropenyl-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas obtained as yellowish crystals, mp. 188-189°.

ISP MS: (MH)⁺ 367.2. NMR: (DMSO, 1H, δ, TMS) 1.28 (t) J=7, 3H), 1.33 (s,6H), 1.86 (s, 3H), 3.49 (s, 2H), 4.00 (q, J=7, 2H), 4.95 (br s, 1H),5.11 (br s, 1H), 5.61 (s, 1H), 5.66 (br s, 2H), 6.04 (br s, 2H), 6.58(d, J=2, 1H), 6.77 (d, J=2, 1H), 7.47 (s, 1H).

The product was prepared in analogy to example 43 but treating, beforeelaborating the diaminopyrimidine ring, the intermediate8-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-2,2-dimethyl-2H-chromene-6-carbaldehydewith 1 eq. of p-toluene sulfonic acid in methylene chloride at 35° for14 hours to give the necessary8-ethoxy-4-isopropenyl-2,2-dimethyl-2H-chromene-6-carbaldehyde.

EXAMPLE 46

3-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-methoxy-2,2-dimethyl-2H-chromen-4-yl]-prop-2-yn-1-olwas prepared in analogy to example 14 but using the methoxy-derivativeas starting material; yellowish crystals, mp. 236-237°.

ISP MS: (MH)⁺ 367.2.

EXAMPLE 47

5-(8-Ethoxy-2,2-dimethyl-4-pyridin-4-yl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 38 but using 4-pyridine boronic acidin step a]; yellow crystals, mp. 223-226°.

ISP MS: (MH)⁺ 404.5. IR (cm⁻¹): 3494, 3382, 2924, 2854, 1646, 1617,1590, 1550, 1450, 1374, 1293, 1151, 1068, 936, 896, 852, 817, 793.

EXAMPLE 48

5-[4-(3,4-Dimethoxy-phenyl)-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 38 but using 3,4-dimethoxyphenylboronic acid; beige crystals, mp. 191-192°.

MS: (M)⁺ 462, (M-CH₃)⁺ 447.

EXAMPLE 49

N-{3-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-phenyl}-acetamidewas prepared in analogy to example 47 but using 3-acetamidophenylboronic acid; yellow crystals, mp. 145° dec.

ISP MS: (MH)⁺ 460.5.

EXAMPLE 50

5-(8-Ethoxy-2,2-dimethyl-4-pyridin-3-yl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine was prepared in analogy to example 38 but usingin step a] pyridine-3-boronic acid 1,3-propanediol cyclic ester; yellowcrystals, mp. 145° dec.

ISP MS: (MH)⁺ 404.5.

EXAMPLE 51

5-(8-Methoxy-2,2-dimethyl-4-thiophen-2-yl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 36 but using the 8-methoxy- insteadof the 8-ethoxy-derivative; yellow crystals, mp. >260°.

MS: (M)⁺ 394, (M-CH₃ 379.

EXAMPLE 52

5-[8-Ethoxy-4-(4-ethoxy-phenyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 38 but using in step a]4-ethoxyphenyl boronic acid; pale yellow crystals, mp. 186-188°.

ISP MS: (MH)⁺ 447.4.

EXAMPLE 53

5-[8-Methoxy-2,2-dimethyl-4-(3-nitro-phenyl)-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 38 but using in step a]3-nitrophenylboronic acid and starting with the methoxy derivative; yellow crystals,mp. 253-254°.

ISP MS: (MH)⁺ 434.5.

EXAMPLE 54

a] [4-(6-Formyl-8-methoxy-2,2-dimethyl-2H-chromen-4-yl)-phenyl]-carbamicacid t-butyl ester

459 mg of (4-bromo-phenyl)-carbamic acid t-butyl ester (1.69 mmol), 536mg of 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](2.11 mmol), 553 mg of potassium acetate (5.63 mmol), and 84.7 mg ofPd(dppf)Cl₂ (0.12 mmol) were mixed together under argon atmosphere in 11ml of abs. DMF and heated for 18 hours to 80°. 394 mg of4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.15mmol), 133 mg of tetrakis-(triphenylphosphine)-palladium (0.12 mmol),and 2.1 ml of 2M potassium phosphate were added and heating continuedfor 18 hours at 80°. The reaction mixture was cooled to roomtemperature, poured onto crushed ice/AcOEt, the organic layer washedwith water and brine, dried over magnesium sulfate and evaporated todryness to afford 523 mg of crude acetal which was cleaved as follows:

The above prepared intermediate was dissolved in 6.4 ml of methanol, 3.2ml of water, and 4.0 ml of THF and treated with 116 mg of pyridiniump-toluene sulfonate (0.4 eq.). After 120 min. at room temperature thereaction mixture was poured onto crushed ice/AcOEt, the organic layerwashed with water and brine, dried over magnesium sulfate and evaporatedto dryness. Flash chromatography (SiO₂ with n-hexane/AcOEt=65/35)produced 357 mg of the title compound as colourless oil.

ISP MS: (MNa)⁺ 432.4, (MNH₄) 427.5, (MH)⁺ 410.4.

b]{4-[6-(2,4-Diamino-pyrimidin-5-ylmethyl)-8-methoxy-2,2-dimethyl-2H-chromen-4-yl]-phenyl}-carbamicacid t-butyl ester

To 353 mg of[4-(6-formyl-8-methoxy-2,2-dimethyl-2H-chromen-4-yl)-phenyl]-carbamicacid t-butyl ester (0.86 mmol) dissolved in 3.8 ml of abs. DMSO and 2.5ml of t-butanol were added 139 mg of 3-anilinopropionitrile (1.1 eq.)and 116 mg of potassium t-butoxide (1.2 eq.), and the reaction wasallowed to proceed for 3 hours at ambient temperature. Pouring ontocrushed ice, twofold extraction with AcOEt, washing with water andbrine, drying over magnesium sulfate and evaporation of the solventsleft 463 mg of crude product which was used as such.

The above prepared crude condensation product was reated with 272 mg ofguanidine hydrochloride (3.3 eq.), 319 mg of potassium t-butoxide (3.3eq.) and 14 ml of ethanol and kept in an oil bath of 80° for 16 hours.The reaction mixture was then poured onto crushed ice, extracted twicewith AcOEt, washed with brine, dried over magnesium sulfate andevaporated to dryness. Flash chromatography (SiO₂ with CH₂Cl₂/MeOH/25%NH₃=19/1/0.05) yielded 47 mg of the title compound as yellow solid, mp.132° dec.

ISP MS: (MH)⁺ 504.3. NMR: (DMSO, 1H, δ, TMS) 1.39 (s, 6H), 1.49 (s, 9H),3.44 (s, 2H), 3.73 (s, 3H), 5.63 (br s, 2H), 5.76 (s, 1H), 6.00 (br s,2H), 6.47 (d, J=2, 1H), 6.78 (d, J=2, 1H), 7.15 (d, J=8.5, 2H), 7.40 (s,1H), 7.47 (d, J=8.5,2H), 9.43 (br s, 1H).

EXAMPLE 55

5-[4-(4-Amino-phenyl)-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 54 but using the 8-ethoxy-derivativeas starting material and cleaving the BOC-group as follows:

54 mg of{4-[6-(2,4-diamino-pyrimidin-5-ylmethyl)-B-ethoxy-2,2-dimethyl-2H-chromen-4-yl]-phenyl}-carbamicacid t-butyl ester (0.10 mmol) were dissolved in 0.8 ml of CH₂Cl₂ andtreated with 0.2 ml of trifluoroacetic acid. After 3 hours the reactionmixture was poured onto crushed ice/NaHCO₃, extracted three times withAcOEt, the organic layer was washed with brine, dried over sodiumsulfate and evaporated to dryness. Crystallization from EtOEt afforded35 mg of the title product as brownish solid, mp. 125° dec.

ISP MS: (MH)⁺ 418.4. NMR: (DMSO, 1H, δ, TMS) 1.29 (t, J=7, 3H),1.37(s,6H),3.44 (s,2H),4.00 (q, J=7, 2H), 5.17 (br s, 2H), 5.55 (s, 1H),5.64 (br s, 2H), 5.99 (br s, 2H), 6.54 (d, J=2, 1H), 6.56 (d, J=8.5,2H), 6.75 (d, J=2, 11H), 6.93 (d, J=8.5, 2H), 7.39 (s, 1H).

EXAMPLE 56

5-[4-(3-Amino-phenyl)-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diaminewas prepared in analogy to example 55 but using(3-bromo-phenyl)-carbamic acid t-butyl ester as starting material;yellow solid, mp. 196-198° dec.

ISP MS: (MH⁺ 418.3.

EXAMPLE 57

5-(8-Ethoxy-2,2-dimethyl-4-methylsulfanyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 4, but commencing the whole sequencewith the, 8-ethoxy-analogue; yellow solid.

ISP MS: (MH)⁺ 373.3.

EXAMPLE 58

5-[(8-Ethoxy-4-(2-thienyl)spiro[2H-1-benzopyran-2,1′-cyclobuten]-6-yl)methyl]-2,4-pyrimidinediaminewas prepared in analogy to example 36 but using4-bromo-8-ethoxy-spiro[2H-1-benzopyran-2,1′-cyclobutan]-6-carboxaldehydeas intermediate; yellow crystals, mp. 202°.

MS: (M)⁺ 420, (M-C₂H₄+392.

EXAMPLE 59

5-(4-Chloro-8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diaminewas prepared in analogy to example 6 but using the ethoxy-derivative asstarting material; yellow crystals, mp. 197-199°.

ISP MS: (MH)⁺ 361.2, 363.2. NMR: (DMSO, 1H, δ, TMS) 1.28 (t, J=7, 3H),1.38 (s, 6H), 3.53 (s, 2H), 4.00 (q, J=7, 2H), 5.68 (br s, 2H), 6.03 (s,1H), 6.08 (br s, 2H), 6.84 (d, J=2, 1H), 6.89 (d, J=2, 1H), 7.52 (s,1H).

EXAMPLE A

Tablets: Sulfamethoxazole 400 mg Compound of formula I, e.g.5-(4-bromo-8-ethoxy-2,2- 80 mgdimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine PRIMOJEL (starchderivative) 6 mg POVIDONE K30 (polyvinylpyrrolidone) 8 mgMagnesiumstearate 6 mg Total weight 500 mg

EXAMPLE B

Tablets: Compound of formula I, e.g. 5-[(4-bromo-8-ethoxyspiro- 100 mg[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4- pyrimidinediamineCorn starch 15 mg Talc 3 mg Magnesiumstearate 2 mg Total weight 120 mg

EXAMPLE C

Injection solutions: Compound of formula I, e.g.5-(8-methoxy-2,2-dimethyl-4- 5 mgmethylsulfanyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4- diamine Glycofurol75 0.2 ml Aq. bidist. sterile ad 1.0 ml

EXAMPLE D

Injection solutions: Compound of formula I, e.g.5-(4-bromo-8-methoxy-2,2- 5 mgdimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine Propylene glycol0.5 ml Aq. bidist. sterile ad 1.0 ml

What is claimed is:
 1. A compound of the formula:

wherein R¹ is alkyl or cycloalkylalkyl; R² and R³ are each independentlyalkyl or cycloalkyl or, taken together with the adjacent carbon atom,represent a saturated 3- to 6-membered carbocyclic or heterocyclic ringbeing unsubstituted or substituted; and R⁴ is hydrogen, halogen, cyano,alkyl, alkylthio, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkynyl,alkoxyalkyl, alkoxyalkynyl, trialkylsilyl, aryl or heteroaryl; orpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein R¹ is methyl or ethyl.
 3. The compound of claim 1, wherein eachof R² and R³ is methyl.
 4. The compound of claim 1, wherein R² and R³taken together with the adjacent carbon atom represent cyclobutyl ortetrahydropyranyl.
 5. The compound of claim 1, wherein R⁴ is bromine. 6.The compound of claim 1, wherein R⁴ is methylthio.
 7. The compound ofclaim 1, wherein said chromene derivative is selected from the groupconsisting of5-(4-bromo-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-[(4-bromo-2′,3′,5′,6′-tetrahydro-8-methoxyspiro[2H-1-benzopyran-2,4′-[4H]pyran]-6-yl)-methyl]-2,4-pyrimidinediamine,5-(8-ethoxy-2,2,4-trimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-(4-chloro-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-(8-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-(8-methoxy-2,2-dimethyl-4-methylsulfanyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-(8-ethoxy-2,2-dimethyl-4-propyl-2H-chromen-6-ylmethyl)-pyrimidine-2,4-diamine,5-[8-methoxy-4-(3-methoxy-prop-1-ynyl)-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diamine,5-[4-(4-fluoro-phenyl)-8-methoxy-2,2-dimethyl-2H-chromen-6-ylmethyl]-pyrimidine-2,4-diamine,5[(4-bromo-8-ethoxyspiro[2H-1-benzopyran-2,1′-cyclobutan]-6-yl)methyl]-2,4-pyrimidinediamine,and5-[4-bromo-8-ethoxy-2,2-dimethyl-2H-chromen-6-lymethyl)-pyrimidine-2,4-diamine.8. A method for making a compound of formula (I) according to claim 1,comprising: reacting a compound of the formula (II)

wherein R¹, R², R³, and R⁴ are as defined in claim 1 and X is a leavinggroup, with a guanidine or a salt thereof to make the compound offormula (I) of claim
 1. 9. The method according to claim 8, furthercomprising: protecting at least one functional group prior to thereaction with said guanidine or said salt thereof; and cleaving saidprotecting group to give said compound of formula (I).
 10. A method formaking a compound of formula (I) of claim 1, comprising: reacting acompound of formula (Ia)

wherein R¹, R², R³, and R⁴ are as defined in claim 1, provided that R⁴is neither a hydrogen atom nor a halogen atom with a compound of theformula (III) R⁴Y  (III) wherein one of X and Y represents a leavinggroup and the other of X and Y represents a group which is eliminatedwith this leaving group, to make the compound of formula (I) of claim 1.11. A pharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of formula (I)

wherein R¹ is alkyl or cycloalkylalkyl; R² and R³ are each independentlyalkyl or cycloalkyl or, taken together with the adjacent carbon atom,represent a saturated 3- to 6-membered carbocyclic or heterocyclic ringbeing unsubstituted or substituted; and R⁴ is hydrogen, halogen, cyano,alkyl, alkylthio, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkynyl,alkoxyalkyl, alkoxyalkynyl, trialkylsilyl, aryl or heteroaryl; orpharmaceutically acceptable salts thereof; and a pharmaceuticallyacceptable carrier.